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original article
Comparison of Four-Drug Regimens and Pairs
of Sequential Three-Drug Regimens as Initial
Therapy for HIV-1 Infection
Robert W. Shafer, M.D., Laura M. Smeaton, M.S.,
Gregory K. Robbins, M.D., M.P.H., Victor De Gruttola, Sc.D., Sally W. Snyder, B.S.,
Richard T. D’Aquila, M.D., Victoria A. Johnson, M.D., Gene D. Morse, Pharm.D.,
Mostafa A. Nokta, M.D., Ana I. Martinez, R.Ph., Barbara M. Gripshover, M.D.,
Pamposh Kaul, M.D., Richard Haubrich, M.D., Mary Swingle, R.N.,
S. Debra McCarty, B.S., Stefano Vella, M.D., Martin S. Hirsch, M.D.,
and Thomas C. Merigan, M.D., for the AIDS Clinical Trials Group 384 Team*
abstract
background
From Stanford University Medical Center,
Stanford, Calif. (R.W.S., T.C.M.); the Harvard School of Public Health (L.M.S.,
V.D.G.) and Harvard Medical School
(G.K.R., M.S.H.) — both in Boston; Social
& Scientific Systems, Silver Spring, Md.
(S.W.S.); the Vanderbilt University Medical Center, Nashville (R.T.D.); the Birmingham Veterans Affairs Medical Center and
the University of Alabama at Birmingham
School of Medicine, Birmingham (V.A.J.);
the State University of New York, Buffalo
(G.D.M.); the University of Texas Medical
Branch, Galveston (M.A.N.); the Division
of AIDS, National Institute of Allergy and
Infectious Diseases, National Institutes of
Health, Bethesda, Md. (A.I.M.); Case Western Reserve University, Cleveland (B.M.G.);
the University of Cincinnati College of
Medicine, Cincinnati (P.K.); the University
of California–San Diego, San Diego (R.H.);
Bristol-Myers Squibb, Plainsboro, N.J.
(M.S.); GlaxoSmithKline, Research Triangle
Park, N.C. (S.D.M.); and the Istituto Superiore di Sanita, Rome (S.V.). Address reprint
requests to Dr. Robbins at Massachusetts
General Hospital, Infectious Disease Unit,
55 Fruit St., Boston, MA 02114, or at
[email protected].
*Other members of the AIDS Clinical Trials Group (ACTG) 384 Team are listed in
the Appendix.
It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should
be initiated with a four-drug or two sequential three-drug regimens.
methods
In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or
zidovudine and lamivudine with therapy involving two consecutive three-drug regimens
the first of which contained either efavirenz or nelfinavir.
results
A total of 980 subjects were followed for a median of 2.3 years. There was no significant
difference in the occurrence of regimen failures between the group that received the
four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the
groups that received the three-drug regimens beginning with didanosine, stavudine,
and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that
received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine,
lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz
(hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first
regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49),
but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21).
conclusions
N Engl J Med 2003;349:2304-15.
Copyright © 2003 Massachusetts Medical Society.
2304
There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among
these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice.
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four-drug regimens and sequential three-drug regimens for hiv-1 infection
reported here are the length of time to the failure of
the initial regimen, the time to virologic failure, the
time to viral suppression, the time to the first severe toxic effect or toxic effect resulting in dose
modification, the change in the CD4 cell count at
weeks 48, 96, and 144, the self-reported level of adherence during the four days before selected clinic
visits,7 and the occurrence of virologic failure accompanied by genotypic drug resistance.
The criterion for regimen failure due to virologic
failure was a lack of adequate viral suppression or virologic rebound. The criterion for regimen failure
due to toxicity was the occurrence of a toxic effect
related to the study medications that could not be
managed with the use of the permitted drug substitutions (stavudine for zidovudine or lamivudine for
didanosine), reductions in the doses, or the temporary discontinuation of the use of a drug.6,8 Peripheral neuropathy was assessed on the basis of a constellation of moderately severe symptoms (of grade
2 or higher) typically beginning in the distal portion
of the legs, including pain, burning sensations,
numbness, and paresthesias.
Testing for genotypic resistance was performed
at the time of regimen failure, provided that the
plasma HIV-1 RNA level was 1000 copies per milliliter or higher, with the use of the Trugene HIV-1
genotyping test (Visible Genetics). Genotypic resistance was defined by the acquisition of mutations
that conferred definite resistance to a drug accordmethods
ing to the manufacturer’s guidelines (version 4.0)
at the time of the failure of the first or second registudy design
AIDS Clinical Trials Group (ACTG) study 384 was a men in groups 1, 2, 3, and 4 or the first regimen in
multicenter, randomized, partially double-blind, groups 5 and 6.
controlled trial in which subjects were randomly assigned to six treatment groups. Groups 1, 2, 3, and statistical analysis
4 received two consecutive three-drug regimens. The general methods for the comparisons with reGroups 5 and 6 each received a four-drug regimen spect to the primary end point and related time(Fig. 1). The criteria for entry, study treatments, and to-event secondary end points are described by
procedures for informed consent, enrollment, and Robbins et al.6 In the comparison of the three-drug
strategies, there was a significant interaction bemonitoring are described by Robbins et al.6
The primary objective of this portion of the study tween the combination of nucleoside analogues
was the comparison of the use of four-drug regi- used in the initial regimen and the use of nelfinavir
mens with the use of two sequential three-drug or efavirenz in the initial regimen. For this reason,
regimens; comparisons were performed separately we report separate comparisons between the fourfor the three-drug strategies starting with a regi- drug regimens and the three-drug strategies startmen containing nelfinavir and those starting with a ing with regimens containing either efavirenz or
regimen containing efavirenz. The primary study nelfinavir according to the combination of nucleoend point was the failure of two consecutive three- side analogues used. We noted significant interacdrug regimens (groups 1, 2, 3, and 4), the failure of tions. Therefore, the significance level for the testa single four-drug regimen (groups 5 and 6), or the ing of hypotheses and the estimation of confidence
premature discontinuation of the study treatment intervals was adjusted to 0.0125, reflecting the perfor any reason (Fig. 1). The secondary end points formance of four different comparisons addressing
a
lthough many drugs are approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection, the cause of the acquired immunodeficiency
syndrome (AIDS), they belong to just four different
classes: nucleoside or nucleotide reverse-transcriptase inhibitors (nucleoside analogues), nonnucleoside reverse-transcriptase inhibitors, protease
inhibitors, and fusion inhibitors. Because crossresistance within a class is common, the failure of
the initial regimen used may compromise the success of future regimens. Indeed, the results of cohort studies suggest that a patient’s first treatment
regimen has the greatest chance of success.1-3
Four-drug antiretroviral regimens containing
drugs from three drug classes have the potential
for increased potency but may also be associated
with increased toxicity, decreased adherence, and
the limitation of subsequent treatment options.4,5
Three-drug regimens containing drugs from only
two classes may be less potent but more tolerable,
and patients treated with regimens that exclude
some classes of drugs may have a better response
to subsequent treatments. We compared the use of
four-drug regimens with the use of sequential pairs
of three-drug regimens. Comparisons among the
pairs of three-drug regimens are presented by Robbins et al. elsewhere in this issue of the Journal.6
n engl j med 349;24
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2305
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the same primary objective.9 Individual confidence
intervals were calculated at 98.75 percent and are reported as adjusted 95 percent confidence intervals.
Post hoc comparisons were made between the
groups receiving four drugs and those receiving two
three-drug regimens with respect to the time to viral
suppression and the occurrence of regimen failure
accompanied by genotypic drug resistance. Additional post hoc analyses considered toxic effects
during treatment with the first two study regimens
in groups 1, 2, 3, and 4 and during treatment with
the single study regimen in groups 5 and 6. Post hoc
assessments of whether the hazard of a first toxic
effect changed over time were performed with the
use of likelihood-ratio tests comparing Weibull
models with exponential models of survival. Exploratory subgroup analyses of the rates of the primary
and related secondary end points according to the
base-line CD4 cell count were performed in the following previously described subgroups: subjects
with fewer than 200 CD4 cells per cubic millimeter,
those with 200 to 350 cells per cubic millimeter, and
those with more than 350 cells per cubic millimeter.4,5 Self-reported adherence was summarized as
the percentage of the prescribed regimen taken during the scheduled sampling periods within the first
32 weeks of study treatment.
results
base-line characteristics
There were 980 subjects included in the analysis:
155 each in groups 1, 2, 3, and 4, 178 in group 5,
and 182 in group 6. A total of 898 subjects were enrolled in the United States, and 82 in Italy. The median age was 36 years, and 82 percent of the subjects
were male. The median base-line plasma HIV-1
RNA level was 4.9 log10 copies per milliliter, and the
median CD4 cell count was 278 per cubic millimeter. The treatment groups were well balanced in
terms of base-line characteristics (see Supplementary Appendix 1, available with the full text of this
article at www.nejm.org).
study follow-up and adherence
The median duration of follow-up was 28 months,
and the median duration of treatment with study
medication was 27 months. The mean self-reported
level of adherence ranged from 97.5 to 98.8 percent,
with no significant differences among the six treatment groups. Stavudine was substituted for zidovudine in 25 subjects, and lamivudine was substituted
for didanosine in 78 subjects.
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Figure 1 (facing page). Study Design and Disposition
of Subjects.
Panel A shows the factorial design of the trial, with the
treatment factors represented in terms of the initial treatment regimens. Panel B shows the numbers of subjects
who were randomly assigned to each group, the numbers of virologic and toxicity-related regimen failures,
and the numbers of premature discontinuations of study
treatment. The primary study end point was defined as
the failure of two consecutive regimens for subjects in
groups 1, 2, 3, and 4 and the failure of a single regimen
for subjects in groups 5 and 6. The premature discontinuation of all study treatment for any reason contributed
to the primary study end point but not to the secondary
end point of the first regimen failure. Panel C lists the
criteria for regimen failure.
primary end point
The primary end point was reached in 441 subjects
(45.0 percent) including 272 in groups 1, 2, 3, and
4 (43.9 percent) and 169 in groups 5 and 6 (46.9 percent) (Fig. 1). Among the 620 subjects in the threedrug groups, the primary study end point was
reached in 80 because of virologic or toxicity-related failure of the second three-drug regimen, and
192 subjects discontinued treatment prematurely
for reasons other than protocol-defined virologic
or toxicity-related failure.6 These 192 subjects included 82 who had virologic or toxicity-related failure of their first regimen. Among the 360 subjects
in the four-drug groups, the primary study end
point was reached in 98 because of virologic failure
(in 63 subjects) or toxicity-related failure (in 35 subjects), and 71 discontinued treatment prematurely
for reasons other than protocol-defined virologic
or toxicity-related failure.
There was no significant difference in the time
to the primary end point between the group that
received the four-drug regimen containing didanosine and stavudine and the group that received sequential three-drug regimens beginning with nelfinavir, didanosine, and stavudine (hazard ratio for
the primary end point in the four-drug group as
compared with the three-drug group, 1.24; adjusted 95 percent confidence interval, 0.82 to 1.87) or
between the four-drug group that received zidovudine and lamivudine and the group that received sequential three-drug regimens beginning with nelfinavir, zidovudine, and lamivudine (hazard ratio,
1.06; adjusted 95 percent confidence interval, 0.71
to 1.58) (Fig. 2A, 2B, and 2C). Similarly, there was
no significant difference in the time to the primary
end point between the group that received the fourdrug regimen containing didanosine and stavudine
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n engl j med 349;24
C
B
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8
Premature
discontinuation
13
Premature
discontinuation
66
9
Premature
discontinuation
12
Premature
discontinuation
29
Premature
discontinuation
30
Premature
discontinuation
63 Virologic
3 Toxicityrelated
Zidovudine
Lamivudine
Nelfinavir
(n=155)
Failures in Group 4
25
Premature
discontinuation
10 Virologic
0 Toxicityrelated
Didanosine
Stavudine
Nelfinavir
(n=19)
4
Premature
discontinuation
12
Premature
discontinuation
22 Virologic
3 Toxicityrelated
Didanosine
Stavudine
Efavirenz
(n=46)
8
Premature
discontinuation
16
Premature
discontinuation
31
66
Failure of First Regimen: Virologic and Toxicity-Related
20 Virologic
11 Toxicityrelated
Zidovudine
Lamivudine
Efavirenz
(n=155)
Failures in Group 3
Group 4
Group 2
Nelfinavir
Second Factor
57
34 Virologic
23 Toxicityrelated
Didanosine
Stavudine
Efavirenz
Nelfinavir
(n=178)
Failures in Group 5
Group 6
Group 5
Efavirenz+nelfinavir
26
Premature
discontinuation
86
41
29 Virologic
12 Toxicityrelated
Zidovudine
Lamivudine
Efavirenz
Nelfinavir
(n=182)
Failures in Group 6
Virologic failure:
Decrease by less than a factor of 10 in HIV-1 RNA level by wk 8
Increase by a factor of more than 10 above nadir measurement (and >2000 copies per milliliter within 24 wk)
HIV-1 RNA level above 200 copies per milliliter in a subject with two previous measurements of less than 200 copies per milliliter, or at any time after wk 24
Toxicity-related failure: severe rash, lactic acidosis, pancreatitis, hepatitis, or any other severe or life-threatening toxic effect; persistence of moderately painful peripheral neuropathy
56
74
83
Primary Study End Point: Virologic or Toxicity-Related Failure or Premature Discontinuation of Therapy
15 Virologic
1 Toxicityrelated
Zidovudine
Lamivudine
Efavirenz
(n=64)
77
58 Virologic
19 Toxicityrelated
Criteria for Failure of Regimen
76
28 Virologic
1 Toxicityrelated
Zidovudine
Lamivudine
Nelfinavir
(n=56)
69
49 Virologic
20 Toxicityrelated
Didanosine
Stavudine
Nelfinavir
(n=155)
26
Premature
discontinuation
Failures in Group 2
Didanosine
Stavudine
Efavirenz
(n=155)
Group 3
Zidovudine + lamivudine
Efavirenz
Group 1
First Factor
Didanosine + stavudine
Failures in Group 1
1st Regimen
2nd Regimen
A
45
Premature
discontinuation
four-drug regimens and sequential three-drug regimens for hiv-1 infection
2307
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and the group that received sequential three-drug
regimens beginning with efavirenz, didanosine, and
stavudine (hazard ratio, 1.01; adjusted 95 percent
confidence interval, 0.68 to 1.50) or between the
four-drug group that received zidovudine and lamivudine and the group that received sequential threedrug regimens beginning with efavirenz, zidovudine, and lamivudine (hazard ratio, 1.45; adjusted
95 percent confidence interval, 0.94 to 2.23) (Fig.
2A, 2D, and 2E).
first regimen failure
The use of a four-drug regimen was associated with
a longer time to the first regimen failure than the
three-drug regimens containing nelfinavir, whether
the subjects were assigned to start treatment with
didanosine and stavudine (hazard ratio for first regimen failure in the four-drug group as compared
with the three-drug group, 0.55; adjusted 95 percent
confidence interval, 0.36 to 0.86) or with zidovudine
and lamivudine (hazard ratio, 0.49; adjusted 95 percent confidence interval, 0.30 to 0.81) (Fig. 3A, 3B,
and 3C). However, the results of the comparisons
between the four-drug regimens and the three-drug
regimens containing efavirenz depended on which
nucleoside analogues were used (P=0.02 for the interaction between the number of drugs and the nucleoside analogues received). The four-drug regimen was associated with a longer time to the first
regimen failure than the three-drug regimen containing efavirenz among the subjects who were
randomly assigned to didanosine and stavudine
(hazard ratio, 0.63; adjusted 95 percent confidence
interval, 0.40 to 0.98), but not among those who
were assigned to zidovudine and lamivudine (hazard ratio, 1.21; adjusted 95 percent confidence interval, 0.67 to 2.20) (Fig. 3A, 3D, and 3E).
first virologic failure
The four-drug regimens were associated with a
longer time to the first virologic failure than the
three-drug strategies beginning with a regimen containing nelfinavir, both among subjects who were
assigned to begin treatment with didanosine and
stavudine (hazard ratio for first virologic failure in
the four-drug group as compared with the threedrug group, 0.49; adjusted 95 percent confidence
interval, 0.31 to 0.78) and among those assigned to
begin treatment with zidovudine and lamivudine
(hazard ratio, 0.41; adjusted 95 percent confidence
interval, 0.25 to 0.68). However, the results of the
comparisons between the four-drug regimens and
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the three-drug strategies beginning with regimens
containing efavirenz depended on which nucleoside
analogues were used (P=0.02 for the interaction).
The four-drug regimen was associated with a longer time to the first virologic failure than the threedrug strategy beginning with a regimen containing
efavirenz among subjects randomly assigned to receive didanosine and stavudine (hazard ratio, 0.57;
adjusted 95 percent confidence interval, 0.35 to
0.93), but not among those assigned to receive zidovudine and lamivudine (hazard ratio, 1.16; adjusted
95 percent confidence interval, 0.63 to 2.14).
time to viral suppression
Suppression of plasma HIV-1 RNA levels to a level
below 50 copies per milliliter occurred faster in
subjects randomly assigned to receive zidovudine,
lamivudine, and efavirenz than among those assigned to the four-drug regimen containing zidovudine, lamivudine, efavirenz, and nelfinavir, but
only among subjects in the highest stratum of HIV-1
RNA (≥5.0 log10 copies per milliliter) (P<0.001).
This effect was not observed within other HIV-1
RNA strata or among the subjects randomly assigned to receive didanosine and stavudine; in fact,
there was a significant interaction among the treatment factors (the use of four drugs or two threedrug regimens and the choice of nucleoside analogues) and the HIV-1 RNA strata (P=0.002). The
cumulative proportions of subjects in whom viral
suppression had been achieved by weeks 16 and
24 were 82 percent and 94 percent, respectively,
among subjects randomly assigned to begin treatment with zidovudine, lamivudine, and efavirenz,
as compared with 68 percent and 84 percent, respectively, among subjects randomly assigned to
receive zidovudine, lamivudine, efavirenz, and nelfinavir (see Supplementary Appendix 2, available
with the full text of this article at www.nejm.org).
The higher rate of viral suppression among the subjects who received zidovudine, lamivudine, and efavirenz did not appear to result from differential
dropout rates among the treatment groups (data
not shown).
cd4 cell counts
The median increase from base line in the CD4 cell
count was 168 cells per cubic millimeter at week 48
(among 795 subjects), 251 cells per cubic millimeter at week 96 (712 subjects), and 295 cells per cubic
millimeter at week 144 (401 subjects). There were
no significant differences in the changes in the CD4
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four-drug regimens and sequential three-drug regimens for hiv-1 infection
A
Probability That the End Point
Has Not Yet Been Reached
1.0
0.9
0.8
Initial regimen
Didanosine, stavudine, and efavirenz
Didanosine, stavudine, and nelfinavir
Zidovudine, lamivudine, and efavirenz
Zidovudine, lamivudine, and nelfinavir
Didanosine, stavudine, efavirenz, and nelfinavir
Zidovudine, lamivudine, efavirenz, and nelfinavir
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
16
32
48
64
80
96 102 128 144 160
Weeks
C
1.0
1.0
0.9
0.9
Probability That the End Point
Has Not Yet Been Reached
Probability That the End Point
Has Not Yet Been Reached
B
0.8
0.7
0.6
0.5
0.4
Hazard ratio=1.24 (CI, 0.82–1.87)
Didanosine, stavudine, and nelfinavir
Didanosine, stavudine, efavirenz,
and nelfinavir
0.3
0.2
0.1
0.0
0.8
0.7
0.6
0.5
0.4
Hazard ratio=1.06 (CI, 0.71–1.58)
Zidovudine, lamivudine, and nelfinavir
Zidovudine, lamivudine, efavirenz,
and nelfinavir
0.3
0.2
0.1
0.0
0
16
32
48
64
80
96 102 128 144 160
0
16
32
48
64
Weeks
80
96 102 128 144 160
Weeks
E
1.0
1.0
0.9
0.9
0.8
0.7
0.6
0.5
0.4
Hazard ratio=1.01 (CI, 0.68–1.50)
Didanosine, stavudine, and efavirenz
Didanosine, stavudine, efavirenz,
and nelfinavir
0.3
0.2
0.1
0.0
Probability That the End Point
Has Not Yet Been Reached
Probability That the End Point
Has Not Yet Been Reached
D
0.8
0.7
0.6
0.5
0.4
Hazard ratio=1.45 (CI, 0.94–2.23)
Zidovudine, lamivudine, and efavirenz
Zidovudine, lamivudine, efavirenz,
and nelfinavir
0.3
0.2
0.1
0.0
0
16
32
48
64
80
96 102 128 144 160
0
16
32
48
64
Weeks
80
96 102 128 144 160
Weeks
Figure 2. Time to the Primary End Point.
The Kaplan–Meier curves show the time to the primary study end point — failure of two consecutive three-drug regimens or a single fourdrug regimen — in all treatment groups (Panel A) and in individual four-drug groups as compared with individual three-drug groups according to the drugs included in the initial regimen (Panels B, C, D, and E). The hazard ratios given are for the primary end point in the four-drug
group as compared with the three-drug group; adjusted 95 percent confidence intervals (CIs) were calculated in order to adjust the significance level to 0.0125 to account for the performance of four comparisons.
n engl j med 349;24
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2309
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A
Probability That the End Point
Has Not Been Reached
1.0
0.9
0.8
Initial regimen
Didanosine, stavudine, and efavirenz
Didanosine, stavudine, and nelfinavir
Zidovudine, lamivudine, and efavirenz
Zidovudine, lamivudine, and nelfinavir
Didanosine, stavudine, efavirenz, and nelfinavir
Zidovudine, lamivudine, efavirenz, and nelfinavir
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
16
32
48
64
80
96 102 128 144 160
Weeks
C
1.0
1.0
0.9
0.9
Probability That the End Point
Has Not Been Reached
Probability That the End Point
Has Not Been Reached
B
0.8
0.7
0.6
0.5
0.4
Hazard ratio=0.55 (CI, 0.36–0.86)
Didanosine, stavudine, and nelfinavir
Didanosine, stavudine, efavirenz,
and nelfinavir
0.3
0.2
0.1
0.0
0.8
0.7
0.6
0.5
0.4
Hazard ratio=0.49 (CI, 0.30–0.81)
Zidovudine, lamivudine, and nelfinavir
Zidovudine, lamivudine, efavirenz,
and nelfinavir
0.3
0.2
0.1
0.0
0
16
32
48
64
80
96 102 128 144 160
0
16
32
48
64
Weeks
80
96 102 128 144 160
Weeks
E
1.0
1.0
0.9
0.9
0.8
0.7
0.6
0.5
0.4
Hazard ratio=0.63 (CI, 0.40–0.98)
Didanosine, stavudine, and efavirenz
Didanosine, stavudine, efavirenz,
and nelfinavir
0.3
0.2
0.1
0.0
Probability That the End Point
Has Not Been Reached
Probability That the End Point
Has Not Been Reached
D
0.8
0.7
0.6
0.5
0.4
Hazard ratio=1.21 (CI, 0.67–2.20)
Zidovudine, lamivudine, and efavirenz
Zidovudine, lamivudine, efavirenz,
and nelfinavir
0.3
0.2
0.1
0.0
0
16
32
48
64
80
96 102 128 144 160
0
Weeks
16
32
48
64
80
96 102 128 144 160
Weeks
Figure 3. Time to the First Regimen Failure.
The Kaplan–Meier curves show the time to the first regimen failure in all treatment groups (Panel A) and in individual four-drug groups as
compared with individual three-drug groups according to the drugs included in the initial regimen (Panels B, C, D, and E). Because most of
the first regimen failures were due to virologic failure, the Kaplan–Meier curves for the time to the first virologic failure were similar to those
shown here. The hazard ratios given are for the first regimen failure in the four-drug group as compared with the three-drug group; adjusted
95 percent confidence intervals (CIs) were calculated in order to adjust the significance level to 0.0125 to account for the performance of four
comparisons.
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four-drug regimens and sequential three-drug regimens for hiv-1 infection
cell count according to the number of drugs used test). Each of the three groups that began therapy
or the combination of nucleoside analogues used with didanosine and stavudine had a higher inci(data not shown).
dence of serious toxic effects than the groups that
began therapy with zidovudine and lamivudine.
deaths, serious adverse events,
This observation prompted a post hoc comparison
and toxic effects of drugs
of the combinations of nucleoside analogues, which
There were six deaths in the three-drug groups and showed that the time to a serious toxic effect was
six deaths in the four-drug groups. Three subjects shorter among subjects who began therapy with
died from myocardial infarction, two from oppor- didanosine and stavudine than among those who
tunistic infection, two from cancer, one from cir- began therapy with zidovudine and lamivudine
rhosis, and one from trauma; the cause of death (P<0.001).
was uncertain in three subjects. There were 44 reTable 1 summarizes the incidence of selected
ported AIDS-defining events in 35 subjects; the in- toxic effects occurring before the primary end point
cidence of a new diagnosis of AIDS or death was according to the assigned treatment group. Periph2.1 per 100 person-years of follow-up. A lower eral neuropathy developed in 154 subjects and was
base-line CD4 cell count and older age (but not a more common in the groups that began therapy
higher HIV-1 RNA stratum at screening or any with didanosine and stavudine than among those
treatment-group assignment) were independently that began therapy with zidovudine and lamivudine
associated with an increased risk of development (P<0.001). The risk of peripheral neuropathy was inof AIDS or death (data not shown).
versely correlated with the base-line CD4 cell count
Between 65 and 104 subjects from each of the (hazard ratio for peripheral neuropathy, 0.86 for
six groups (42 to 58 percent) had a serious toxic ef- every increment of 100 cells per cubic millimeter in
fect (a severe toxic effect or a toxic effect resulting the CD4 cell count; 95 percent confidence interval,
in dose modification) during treatment with their 0.79 to 0.95). Among the subjects who began therfirst regimen, and there was a significant differ- apy with didanosine and stavudine, the risk of a first
ence across the six groups (P<0.001 by the log-rank serious toxic effect decreased over time (P=0.001).
Table 1. Selected Toxic Effects According to Treatment Group.*
Toxic Effects
All Groups
(N=980)
Group 1
(N=155)
Group 2
(N=155)
Group 3
(N=155)
Group 4
(N=155)
Group 5
(N=178)
Group 6
(N=182)
Pancreatitis
18 (1.8)
7 (4.5)
6 (3.9)
1 (0.6)
1 (0.6)
2 (1.1)
1 (0.5)
Elevated serum lipase level
99 (10.1)
23 (14.8)
20 (12.9)
13 (8.4)
9 (5.8)
20 (11.2)
14 (7.7)
154 (15.7)
41 (26.5)
29 (18.7)
10 (6.5)
16 (10.3)
42 (23.6)
16 (8.8)
Rash
113 (11.5)
22 (14.2)
17 (11.0)
16 (10.3)
16 (10.3)
19 (10.7)
23 (12.6)
Central nervous system effects
122 (12.4)
18 (11.6)
22 (14.2)
20 (12.9)
21 (13.5)
16 (9.0)
25 (13.7)
Gastrointestinal effects
68 (6.9)
10 (6.5)
20 (12.9)
6 (3.9)
11 (7.1)
11 (6.2)
10 (5.5)
Hepatic effects
62 (6.3)
12 (7.7)
16 (10.3)
4 (2.6)
7 (4.5)
14 (7.9)
9 (4.9)
Hematologic effects
34 (3.5)
3 (1.9)
7 (4.5)
8 (5.2)
6 (3.9)
3 (1.7)
7 (3.8)
number of subjects (percent)
Peripheral neuropathy
* Group 1 initially received didanosine, stavudine, and efavirenz; group 2 initially received didanosine, stavudine, and nelfinavir; group 3 initially received zidovudine, lamivudine, and efavirenz; group 4 initially received zidovudine, lamivudine,
and nelfinavir; group 5 received didanosine, stavudine, efavirenz, and nelfinavir; and group 6 received zidovudine, lamivudine, efavirenz, and nelfinavir. Pancreatitis was defined clinically. Data were collected for elevated serum lipase levels
(>1.5 times the upper limit of normal), peripheral neuropathy, rash, and central nervous system toxic effects, and data on
effects of grade 2 or higher are shown. Data on gastrointestinal toxic effects, hepatic toxic effects (elevated serum aspartate aminotransferase, serum alanine aminotransferase, or total bilirubin levels), and hematologic toxic effects of grade
3 or higher are shown. Central nervous system symptoms included agitation, confusion, depression, lightheadedness,
abnormal level of consciousness, and sleeping abnormalities. Gastrointestinal symptoms included nausea, vomiting,
and diarrhea. Peripheral neuropathy, pancreatitis, elevated lipase, and hepatic abnormalities were significantly more likely to occur in groups that began therapy with didanosine and stavudine than in groups that began therapy with zidovudine and lamivudine (P<0.001 for peripheral neuropathy, P=0.005 for pancreatitis, P=0.003 for elevated serum lipase
levels, and P=0.004 for hepatic abnormalities).
n engl j med 349;24
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2311
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new england journal
Post hoc analyses showed a greater risk of pancreatitis (P=0.005), elevated serum lipase levels
(P=0.003), and hepatic abnormalities (P=0.004)
among subjects who were randomly assigned to
begin therapy with didanosine and stavudine than
among those assigned to begin therapy with zidovudine and lamivudine (Table 1). The occurrence
of lactic acidosis during treatment with study medications was reported in nine subjects, all of whom
were receiving didanosine and stavudine. There
was no significant difference in the time to a toxic
effect according to whether subjects began therapy
with nelfinavir, efavirenz, or both.
genotypic drug resistance
Mutations conferring resistance to nucleoside analogues were detected at positions 184 (in 80 percent
of cases), 74 (in 5 percent), 65 (in 3 percent), 215 (in
3 percent), 75 (in 1 percent), and 151 (in 1 percent)
and at more than one of these positions in 5 percent
of subjects with nucleoside-analogue resistance.
Resistance to nucleoside analogues developed in
significantly fewer subjects in the four-drug group
than in the three-drug group that began therapy
with nelfinavir among subjects who began therapy
with didanosine and stavudine (0.6 percent vs. 7.1
percent, P=0.001) and among those who began
therapy with zidovudine and lamivudine (3.8 percent vs. 22.6 percent, P<0.001) (Fig. 4A). The effect
of starting treatment with a four-drug regimen or a
three-drug regimen containing efavirenz depended on the combination of nucleoside analogues
used (P=0.003 for the interaction): resistance to nucleoside analogues developed in significantly fewer
subjects in the four-drug group than in the threedrug group that began therapy with efavirenz
among subjects who began therapy with didanosine and stavudine (0.6 percent vs. 16.1 percent,
P<0.001) but not among those who began therapy
with zidovudine and lamivudine (3.8 percent vs.
7.7 percent, P=0.12) (Fig. 4A). Among subjects in
three-drug groups, those who began therapy with
zidovudine, lamivudine, and efavirenz had fewer
treatment failures with resistance to nucleoside analogues (7.7 percent) than those who began therapy with zidovudine, lamivudine, and nelfinavir (22.6
percent, P<0.001) or those who began therapy with
didanosine, stavudine, and efavirenz (16.1 percent,
P=0.02) (Fig. 4A).
Mutations conferring resistance to nonnucleoside reverse-transcriptase inhibitors were detected at
positions 103 (in 72 percent of cases), 190 (in 6 percent), and 188 (in 3 percent) and at more than one of
2312
n engl j med 349;24
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medicine
these positions in 19 percent of subjects with resistance to nonnucleoside reverse-transcriptase inhibitors. Resistance to nonnucleoside reverse-transcriptase inhibitors developed in significantly fewer
subjects in the four-drug group than in the threedrug group that began therapy with efavirenz
among subjects who began therapy with didanosine and stavudine (10.7 percent vs. 23.9 percent,
P=0.001) but not among those who began therapy
with zidovudine and lamivudine (8.2 percent vs.
7.1 percent, P=0.69) (Fig. 4B). There was no significant difference in the rate of resistance to nonnucleoside reverse-transcriptase inhibitors between the
four-drug groups and the three-drug groups that
began therapy with nelfinavir (Fig. 4B). The results
of comparisons among the three-drug groups depended on the combination of nucleoside analogues used (P=0.006 for the interaction). Among
the subjects in three-drug groups, resistance to nonnucleoside reverse-transcriptase inhibitors developed in a higher proportion of those who began
therapy with didanosine, stavudine, and efavirenz
(23.9 percent) than of those who began therapy with
didanosine, stavudine, and nelfinavir (5.2 percent,
P<0.001) or those who began therapy with zidovudine, lamivudine, and efavirenz (7.1 percent, P<
0.001) (Fig. 4B).
Mutations conferring resistance to protease inhibitors were detected at positions 30 (in 61 percent of cases), 90 (in 17 percent), 46 (in 7 percent),
and 84 (in 3 percent) and at more than one of these
positions in 12 percent of subjects with resistance
to protease inhibitors. Resistance to protease inhibitors developed in fewer subjects in the four-drug
group than in the three-drug group that began
therapy with nelfinavir among subjects who began
therapy with didanosine and stavudine (2.2 percent vs. 11.0 percent, P=0.001) and among those
who began therapy with zidovudine and lamivudine (0.5 percent vs. 7.7 percent, P<0.001) (Fig. 4C).
There was no significant difference in the rate of
resistance to protease inhibitors between the fourdrug groups and the three-drug groups that began
therapy with efavirenz (Fig. 4C).
discussion
This study compared different strategies for initiating antiretroviral therapy with four-drug and sequential three-drug regimens, with use of a composite primary end point of virologic rebound, toxic
effects, or premature discontinuation of treatment,
as well as seven secondary end points, including the
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four-drug regimens and sequential three-drug regimens for hiv-1 infection
A
30
25
20
15
10
5
0
30
25
20
15
10
5
0
Didanosine
+Stavudine
P<0.001
P=0.001
P=0.12
P<0.001
Efavirenz
Nelfinavir
Zidovudine
+Lamivudine
Resistance to Nucleoside Analogues (%)
Figure 4. Proportions of Subjects Who Had Regimen Failure with Resistance to Nucleoside Analogues (Panel A),
Nonnucleoside Reverse-Transcriptase Inhibitors (Panel
B), and Protease Inhibitors (Panel C) According to Treatment Group.
For subjects in groups 1, 2, 3, and 4, the bars show the
cumulative proportions of subjects with drug resistance
at the time of the first or second regimen failure; for subjects in groups 5 and 6, the bars show the proportions of
subjects with new drug-resistance mutations after the
failure of their first regimen. Drug-resistance mutations
were identified through the sequencing of the HIV-1 reverse transcriptase and protease of virus isolated from
subjects with virologic failure or toxicity-related failure
who had plasma HIV-1 RNA levels of at least 1000 copies
per milliliter.
Efavirenz
+Nelfinavir
n engl j med 349;24
30
25
20
15
10
5
0
30
25
20
15
10
5
0
Didanosine
+Stavudine
P=0.001
P=0.07
Zidovudine
+Lamivudine
P=0.69
P=0.53
Efavirenz
Nelfinavir
Efavirenz
+Nelfinavir
C
30
25
20
15
10
5
0
30
25
20
15
10
5
0
Didanosine
+Stavudine
P=0.25
P=0.001
P=0.36
Zidovudine
+Lamivudine
Resistance to Protease Inhibitors (%)
change in the CD4 cell count, the first regimen failure (due to virologic rebound or toxic effects), the
first virologic failure, the time to an undetectable
HIV-1 RNA level, toxic effects, the level of adherence, and the development of drug resistance. Because no single surrogate end point has been validated as capturing the clinical benefit of prolonged
treatment and because low rates of clinical events
preclude the use of such end points for the investigation of first-line therapy, we looked for consistent
results among the end points.
There was no significant difference in the duration of successful treatment, as measured in terms
of the time to the primary end point, between the
groups receiving a single four-drug regimen and
those receiving two consecutive three-drug regimens, regardless of the combination of nucleoside
analogues used in the initial regimen. There were
also no significant differences between the fourdrug groups and the three-drug groups in the
changes in the CD4 cell count. The definition of the
primary end point was designed to capture all possible reasons for the premature discontinuation of
treatment in addition to virologic rebound and protocol-specified toxic effects. Because the primary
end point was the time to the failure of drugs from
all three classes, subjects receiving a four-drug regimen reached the primary end point when they had
a single regimen failure (involving the use of only a
single combination of nucleoside analogues).
In terms of the time to the secondary end points
of the first regimen failure and the first virologic
failure, the four-drug regimens were superior both
to the three-drug strategies beginning with regimens containing nelfinavir and to therapy beginning with didanosine, stavudine, and efavirenz, but
Resistance to Nonnucleoside
Reverse-Transcriptase Inhibitors (%)
B
P<0.001
Efavirenz
Nelfinavir
Efavirenz
+Nelfinavir
not to therapy beginning with zidovudine, lamivudine, and efavirenz. There were relatively few first
regimen failures during the three-year study in the
group that began therapy with zidovudine, lamivudine, and efavirenz. The potency of this regimen
was further demonstrated by the finding that the
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2313
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new england journal
use of this regimen resulted in a shorter time to viral
suppression than either of the four-drug regimens
among subjects with the highest levels of HIV-1
RNA. Although the addition of nelfinavir to these
three drugs provided no further benefit with respect
to any end point, we cannot rule out the possibility
that a different protease inhibitor might have been
more effective.
There was no significant difference in the risk of
toxic effects between the four-drug groups and the
three-drug groups. Only the combination of nucleoside analogues used in the initial regimen significantly influenced the risk of toxic effects, with a
higher incidence of peripheral neuropathy, pancreatitis, and hepatic enzyme abnormalities among subjects who began therapy with didanosine and stavudine than among those who began therapy with
zidovudine and lamivudine. Preliminary data from
a subgroup of subjects have also shown a greater degree of fat loss in the limbs among subjects who began therapy with didanosine and stavudine.10 All
these toxic effects may result from mitochondrial
dysfunction induced by nucleoside analogues.11-13
Antiretroviral regimens containing drugs from
more than two classes are not routinely recommended for patients beginning antiretroviral therapy because of concern that patients in whom a
three-class regimen fails may be at higher risk for
drug resistance should virologic failure occur, leaving them with fewer options for subsequent therapy. However, we found that the cumulative proportion of regimen failures with genotypic resistance
was often lower, and never higher, in the four-drug
groups than in the three-drug groups.
Reported adherence was high in each of the six
groups, suggesting that the study’s findings result
from the intrinsic activity of the treatment regimens
rather than from the patterns of adherence. Our
findings, however, may not be applicable to persons
who do not maintain high levels of adherence.14
Treatment failure and resistance to efavirenz and lamivudine are usually caused by mutations of a single amino acid,15,16 whereas resistance to protease
inhibitors frequently requires multiple amino acid
substitutions.4,17-20 In this study, subjects in whom
regimens containing efavirenz failed often had amino acid substitutions that would also confer resistance to other nonnucleoside reverse-transcriptase
inhibitors. In contrast, resistance to protease inhib-
of
medicine
itors was often associated with a mutation at position 30 of the protease gene that confers resistance
to nelfinavir alone.
Although four-drug regimens were effective
and did not lead to an increased risk of toxic effects
or drug resistance, the simpler three-drug regimen
consisting of zidovudine, lamivudine, and efavirenz emerged as the optimal choice for the initiation of therapy. This three-drug regimen was effective in achieving and maintaining viral suppression
throughout the study and allowed most subjects
who began therapy with this regimen to reserve
protease-inhibitor therapy for the future. The fact
that the addition of nelfinavir to this three-drug
regimen did not lead to more rapid viral suppression attests to the potency of this regimen; possible
mechanisms underlying this potency are being explored in a pharmacologic substudy. Zidovudine, lamivudine, and efavirenz was the most effective of
the initial three-drug regimens in terms of delaying
the first regimen failure,6 and this was also the only
three-drug regimen that was not significantly different from the four-drug regimens in terms of the
lengths of time to the first regimen failure and the
first virologic failure.
Supported in part by grants (AI38858 and AI38855) from the National Institute of Allergy and Infectious Diseases; by the General
Clinical Research Center Units funded by grants (RR00070,
RR00052, RR00044, and RR05096) from the National Center for
Research Resources; by a grant (to the Istituto Superiore di Sanita)
from the HIV Clinical Research Programme; and by virology laboratory contracts (201VC001 with Vanderbilt University, 200VC001
with the University of Alabama at Birmingham, and 200VC011 with
Stanford University).
Dr. D’Aquila reports having served as a consultant for or having
received honorariums from Agouron, Bristol-Myers Squibb, Gilead,
GlaxoSmithKline, ViroLogic, and Visible Genetics; Dr. De Gruttola
having served as a consultant for GlaxoSmithKline and Tibotec–Virco; Dr. Haubrich having served as a consultant for or having received
honorariums from Agouron, Bristol-Myers Squibb, and GlaxoSmithKline; Dr. Johnson having served as a consultant for or having
received honorariums from Abbott, Bristol-Myers Squibb, GlaxoSmithKline, and ViroLogic; Dr. Gripshover having served as a consultant for or having received honorariums from Abbott, BristolMyers Squibb, Gilead, and Roche and having received grant support
from Boehringer–Ingleheim; Dr. Hirsch having served as a consultant for Bristol-Myers Squibb and GlaxoSmithKline; Dr. Merigan
holding equity in Bristol-Myers Squibb and Pfizer and having received grant support from Hoffmann–LaRoche; Dr. Morse having
served as a consultant for or having received honorariums or grant
support from Agouron, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, and Roche; Dr. Robbins having served as a consultant for or
having received honorariums from Agouron, Bristol-Myers Squibb,
and GlaxoSmithKline; and Dr. Shafer having served as a consultant
for or having received honorariums from Bristol-Myers Squibb, and
GlaxoSmithKline and having received grant support from Agouron,
Bristol-Myers Squibb, and GlaxoSmithKline.
ap p e n d i x
Other members of the ACTG 384 team were M. Fischl (Miami University), R. Pollard (University of Texas, Galveston), M. Dubé (Indiana University), C. Pettinelli (National Institutes of Health), R. Delapenha (Howard University), B. Putnam (University of Colorado), M. Klebert
(Washington University), M. Testa (Harvard School of Public Health), A. Chiesi, C. Tomino (Istituto Superiore de Sanita), S. Deeks (Univer-
2314
n engl j med 349;24
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Copyright © 2003 Massachusetts Medical Society. All rights reserved.
four-drug regimens and sequential three-drug regimens for hiv-1 infection
sity of California, San Francisco), T. Nevin (Social & Scientific Systems), J. Levin, V. French, O. Fennell (Adult AIDS Clinical Trials Group
Community Constituency Group), M. Stevens, R. Grosso, B. Dusak, S. Hodder (Bristol-Myers Squibb), J. Tolson, C. Brothers (GlaxoSmithKline), R. Leavitt (Merck), D. Manion, N. Ruiz, K. Morrissey (DuPont Pharmaceuticals), M. Becker, B. Quart (Agouron), C. Jennings (Northwestern University), L. Gedeon, S. Dascomb, M. Cooper, M. Murphy, K. Blakelock (Frontier Science and Technology Foundation), A. Doolan (Massachusetts General Hospital).
The following persons and institutions participated in the conduct of this trial: T. Powell, L. Simmermacher, J. Robinson (University of
Cincinnati), L. Alexis, J. Brown, Y. Butler, C. St. Paul (Howard University), L. Meixner, T. Gilbert (University of California, San Diego), J. Kaufman, A. Chall, S. Pedersen, J. Horton (Carolinas Medical Center), T. Lane (Moses Cone Hospital), J. Castro, L. Thompson, L. Colon (University
of Miami), M. Chance, J. Baum (Case Western Reserve University), D. Wininger, D. Gochnour (Ohio State University), C. Funk, D. Johnson
(University of Southern California), I. Matozzo, I. Frank, K. Maffei, D. Kim (University of Pennsylvania), S. Marrero, O. Mendez, I. Torres, N.
Rabell (University of Puerto Rico), G. Casey, C. Derkowski (University of Texas, Galveston), C. Fietzer, R. Nelson, K. Fox, R. Sanders (University of Minnesota), W. Wallace (University of Iowa), S. Swindells (University of Nebraska), H. Rominger, J. Richardson (Indiana University
Hospital), P. Tebas, D. DeMarco, M. Royal (Washington University), B. Berzins (Northwestern University), H. Kessler (Rush–Presbyterian–St.
Luke’s Medical Center), J. Forcht, D. Tolenaar, C. Talabucon, C. Gonzalez (New York University/Bellevue), S. Wright, J. Graham (University of
Alabama, Birmingham), C. Basler, S. Canmann (University of Colorado Health Sciences Center), P. Cain, S. Stoudt, J. Norris, S. Valle (Stanford
University), S. Tedder, C. Hamilton (Duke University Medical Center), T. Flynn, K. Hartman (Massachusetts General Hospital), H. Fitch (Beth
Israel Deaconess Medical Center), T. Cooley (Boston Medical Center and Harvard University), J. Frederick, S. Souza (University of Hawaii), D.
Baker, A. Weiss, B. Becker, I. Wiggins (Johns Hopkins University), R. Reichman, M. Shoemaker, R. Hewitt, T. O’Hara (University of Rochester
Medical Center), J. Lertora, R. Clark, M. Beilke, J. Dumestre (Tulane University), A. Moe, M. Witt, M. Guerrero, T. Maldonado (University of
California, Los Angeles), A. Collier, B. Royer, J. Stekler, J. Conley (University of Washington), M. Dolan, E. Chusid, H. Sacks, I. Lowy (Mt. Sinai
Medical Center), M. Jacobson, J. Volinski (San Francisco General Hospital), T. Stroberg, R. Gulick, M. Glesby, V. Hughes (Cornell University),
R. Arcieri, M. Pirillo, C. Galluzzo, E. Germinario, R. Amici, M. Marzi, A. Nobile, R. Di Nallo, C. Polizzi (Istituto Superiore di Sanita), O. Coronado, G. Fasulo (Ospedale Maggiore), G. Carosi, F. Castelli (Università degli Studi di Brescia Spedali Civili di Brescia), M. Di Pietro, F. Vichi
(Ospedale Santa Maria Annunziata), G. Sterrantino, S. Ambu (Azienda Ospedaliera Careggi), M. Cargnel, P. Meraviglia, F. Niero, A. Capetti, A.
D’Arminio Monforte, S. Sollima, C. Balotta (Ospedale Luigi Sacco), S. Delia, M. Ciardi, G. d’Ettore, G. Forcina (Università degli Studi di Roma
La Sapienza Policlinico Umberto I), M. Soranzo, A. Macor (Ospedale Amadeo Di Savoia), D. Bassetti, A. Di Biagio (Università di Genova), L.
Minoli, R. Maserati (Istituto di Recovero e Cura a Caratterre Scientifico Policlinico S. Matteo), F. Ghinelli, L. Sighinolfi (Azienda Arcispedale
Sant’ Anna), A. Riva, G. Scalise (Università degli Studi di Ancona Ospedale Umberto I), D. Santoro, E. Rinaldi (Ospedale Sant’ Anna), F.
Chiodo, M. Borderi (Policlinico Sant’ Orsola Malpighi), G. Guaraldi, R. Esposito (Università degli Studi di Modena), C. Ferrari, G. Pasetti
(Azienda Ospedaliera di Parma), N. Abrescia, A. Busto, A. Chirianni, M. Gargiulo, C. Izzo, C. Sbreglia (Azienda Ospedaliera D. Cotugno), F.
Alberici, D. Sacchini (Azienda Unitá Sanitaria Locale di Piacenza Ospedale Civile), G. Magnani, G. Zoboli (Arcispedale Santa Maria Nuova).
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